Issues

Humans are disomic, with paired maternal and paternal autosomes presumed equally expressed. Autosomal random monoallelic expression challenges this paradigm and may underlie incomplete penetrance in diverse genetic diseases while allowing for personal evolution within the inherited genetic constraints.

Myeloid cells infiltrate tumors from early transformation to advanced disease; however, their plasticity complicates therapeutic targeting. Emerging technologies uncover unexpected cellular states and functions, as discussed by Nogales-Pons and colleagues. Shaped by tumor cues, tissue architecture, and temporal dynamics, these insights redefine myeloid diversity and pave the way for more precise, future-oriented cancer immunotherapy strategies.

This study identifies hypoxia-inducible protein 2 (HIG2) as a key regulator of anti-inflammatory property of Ly6C^highLy6G^low monocyte-derived macrophages in the ischemic brain after stroke through mediating phosphatidylcholine synthesis. Targeting HIG2 might represent a novel immunometabolic strategy to reduce poststroke neuroinflammation.

This study reveals that NIK expression in circulating myeloid cells is essential for EAE development. NIK drives neuroantigen-specific T cell priming by regulating antigen presentation and IL-23 production, identifying NIK as a key orchestrator of myeloid-driven CNS autoimmunity.

Birui et al. identify Zbtb32 as a key promoter of terminally exhausted CD8⁺ T cell differentiation, enhancing cell cytotoxicity and anti-tumor function. This study reveals the potential interplay and regulation within CD8⁺ T cell regulatory network, providing valuable insights for cancer immunotherapy.

Defective intron recycling leads to the accumulation of intron-derived double-stranded RNA in the cytoplasm, which suppresses PKR and RNase L activation. This work reveals how intronic Alu repeats and RNA metabolism shape endogenous dsRNA levels and cell-intrinsic immunity.

IFNγ induces long-lasting memory in macrophages, which is generally assumed to be maintained by their epigenome. Gorin et al. report that IFNγ-induced enhancers and potentiated stimulus-response capabilities are, in fact, maintained by persistent JAK/STAT signaling from cytokine sequestered at the cell surface.

Chin et al. discovered that macrophage-specific Ak4 regulates mtDNA synthesis, through which it controls mitochondrial biogenesis and mtROS levels and, subsequently, bacterial killing. Their study highlights the vital role of Ak4 in macrophage defense against pathogenic bacteria.

This study uses a novel mouse model to identify CD8 T cell–derived TNF as a key driver of immune checkpoint inhibitor–induced myocarditis and highlights receptor-selective TNF blockade as a therapeutic approach to prevent cardiotoxicity without compromising antitumor immunity.

During intestinal mucosal inflammation, enteric neurons recruit monocytes to the extra-mucosal myenteric plexus of the enteric nervous system (ENS), where monocyte-derived macrophages contribute to its pathological remodeling. This neuroimmune inflammatory axis is counterbalanced by a hypoxia-induced stress response in enteric neurons, thereby preserving ENS integrity and offering a therapeutic strategy for its protection during inflammation.

Nasal vaccination aims to generate local protection from airborne pathogens in the upper airway mucosal tissues. Liu et al. demonstrate that B cells in the NALT depend on B cell receptor affinity and CCR6 for positioning in the NALT subepithelial dome, class switching to IgA, and effective GC seeding.

Although sensory nerves respond differentially to individual inflammatory cytokines, it is unknown whether these relay to distinct central circuits governing physiological responses. This work identifies such a circuit in which IL-1β–responsive neurons control multiple components of the stress response.

Golec et al. describe a PI3 Kinase-Foxo1-FasL signaling circuit that promotes amplified signaling and rewires transcriptional and epigenetic programs driving IFN-γ and altered T helper cell differentiation in CD4⁺ T cells from mice expressing an activating mutant of phosphoinositide 3-kinase delta.

Ostendorf et al. show that activation of liver-X-receptors preconditions T cells to render them more receptive to adopting effector states upon activation. This effect can be therapeutically harnessed to enhance anti-tumor immunity by enhancing T cell priming.

Bub et al. use single-cell RNA sequencing and new macrophage depletion models to discover niche-derived signals that promote monocyte-derived macrophages. They identify oxysterols sensed through GPR183 as metabolic cues that instruct monocytes to establish residence in lung macrophage niches.

Patients with autoimmune hepatitis have a unique autoantibody signature, yielding clues about disease pathophysiology, including evidence for cross-reactivity with a common herpesvirus, human herpesvirus 6, and antibodies targeting the antifibrotic relaxin receptor with potential to promote fibrosis progression.

David et al. investigate whether the common HAQ STING allele explains clinical non-penetrance in COPA syndrome. In a separate cohort, they identify asymptomatic individuals lacking the HAQ allele and an HAQ-positive COPA patient with kidney disease, suggesting that STING haplotype alone does not fully account for disease expression in COPA syndrome.

In this issue of JEM, Golec et al. report that a mutation of PI-3 kinase underlying APDS impairs type 2 immunity. Surprisingly, mice with this mutation have disordered responses to allergic insults, with enhanced production of IFN-γ and a decrease in Th2 cytokines.

Innate immune cells can retain molecular imprints of past encounters long after the initial stimulus has ceased. In this issue, Gorin et al. reveal an unexpected mechanism by which IFN-γ sustains trained immune states through prolonged signaling driven by cytokine retention at the cell surface.